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BACKGROUND: Hypoxaemia occurs frequently during paediatric laryngeal microsurgery. OBJECTIVE: The oxygen reserve index is a noninvasive and continuous parameter to assess PaO2 levels in the range of 100 to 200âmmHg. It ranges from 0 to 1.0. We investigated whether monitoring the oxygen reserve index can reduce the incidence of SpO2 90% or less. DESIGN: Randomised controlled trial. SETTING: A tertiary care paediatric hospital. PARTICIPANTS: Paediatric patients aged 18âyears or less scheduled to undergo laryngeal microsurgery. INTERVENTION: The patients were randomly allocated to the oxygen reserve index or control groups, and stratified based on the presence of a tracheostomy tube. Rescue intervention was performed when the oxygen reserve index was 0.2 or less and the SpO2 was 94% or less in the oxygen reserve index and control groups, respectively. MAIN OUTCOME MEASURE: The primary outcome was the incidence of SpO2 90% or less during the surgery. RESULTS: Data from 88 patients were analysed. The incidence of SpO2 ≤â90% did not differ between the oxygen reserve index and control groups [Pâ=â0.114; 11/44, 25% vs. 18/44, 40.9%; relative risk: 1.27; and 95% confidence interval (CI): 0.94 to 1.72]. Among the 128 rescue interventions, SpO2 ≤â90% event developed in 18 out of 75 events (24%) and 42 out of 53 events (79.2%) in the oxygen reserve index and control groups, respectively (Pâ<â0.001; difference: 55.2%; and 95% CI 38.5 to 67.2%). The number of SpO2 ≤â90% events per patient in the oxygen reserve index group (median 0, maximum 3) was less than that in the control group (median 0, maximum 8, Pâ=â0.031). CONCLUSION: Additional monitoring of the oxygen reserve index, with a target value of greater than 0.2 during paediatric airway surgery, alongside peripheral oxygen saturation, did not reduce the incidence of SpO2 ≤â90%.
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Hipoxia , Saturación de Oxígeno , Humanos , Masculino , Femenino , Hipoxia/prevención & control , Hipoxia/sangre , Hipoxia/etiología , Preescolar , Oxígeno/sangre , Niño , Lactante , Microcirugia/métodos , Laringe , Oximetría/métodos , Monitoreo Intraoperatorio/métodos , AdolescenteRESUMEN
Pulmonary benign metastasizing leiomyoma is an uncommon condition, predominantly affecting women of childbearing age with a history of uterine smooth muscle tumors and uterine leiomyoma surgery for uterine leiomyoma. The progression of PBML is often unpredictable and depends on the extent of lung involvement. Generally, most patients remain asymptomatic, but a minority may experience coughing, wheezing, or shortness of breath, which are frequently misdiagnosed as pneumonia. consequently, this presents significant challenges in both treatment and nursing care before diagnosis. This paper reports the case of a 35-year-old woman primarily diagnosed with acute hypoxic respiratory failure who was transferred from the emergency room to the intensive care unit. The initial computed tomography scan of the patient's lungs indicated diffuse interstitial pneumonia, but the sequencing of the alveolar lavage fluid pathogen macro did not detect any bacteria, fungi, or viruses. Moreover, the patient remained in a persistent hypoxic state before the definitive diagnosis. Therefore, our focus was on maintaining the airway patency of the patient, using prone ventilation, inhaling nitric oxide, monitoring electrical impedance tomography, and preventing ventilator-associated pneumonia to improve oxygenation, while awaiting immunohistochemical staining of the patient's biopsied lung tissue. This would help us clarify the diagnosis and treat it based on etiology. After meticulous treatment and nursing care, the patient was weaned off the ventilator after 26 days and transferred to the respiratory ward after 40 days. This case study may serve as a reference for clinical practice and assist patients suffering from PBML.
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Leiomioma , Neoplasias Pulmonares , Insuficiencia Respiratoria , Neoplasias Uterinas , Humanos , Femenino , Adulto , Leiomioma/patología , Leiomioma/complicaciones , Leiomioma/diagnóstico , Insuficiencia Respiratoria/etiología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Neoplasias Uterinas/patología , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/diagnóstico , Tomografía Computarizada por Rayos X , Hipoxia/etiología , Diagnóstico DiferencialRESUMEN
BACKGROUND: High levels of lactate are positively associated with prognosis and mortality in pulmonary hypertension (PH). Lactate dehydrogenase A (LDHA) is a key enzyme for the production of lactate. This study is undertaken to investigate the role and molecular mechanisms of lactate and LDHA in PH. METHODS: Lactate levels were measured by a lactate assay kit. LDHA expression and localization were detected by western blot and Immunofluorescence. Proliferation and migration were determined by CCK8, western blot, EdU assay and scratch-wound assay. The right heart catheterization and right heart ultrasound were measured to evaluate cardiopulmonary function. RESULTS: In vitro, we found that lactate promoted proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in an LDHA-dependent manner. In vivo, we found that LDHA knockdown reduced lactate overaccumulation in the lungs of mice exposed to hypoxia. Furthermore, LDHA knockdown ameliorated hypoxia-induced vascular remodeling and right ventricular dysfunction. In addition, the activation of Akt signaling by hypoxia was suppressed by LDHA knockdown both in vivo and in vitro. The overexpression of Akt reversed the inhibitory effect of LDHA knockdown on proliferation in PASMCs under hypoxia. Finally, LDHA inhibitor attenuated vascular remodeling and right ventricular dysfunction in Sugen/hypoxia mouse PH model, Monocrotaline (MCT)-induced rat PH model and chronic hypoxia-induced mouse PH model. CONCLUSIONS: Thus, LDHA-mediated lactate production promotes pulmonary vascular remodeling in PH by activating Akt signaling pathway, suggesting the potential role of LDHA in regulating the metabolic reprogramming and vascular remodeling in PH.
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Proliferación Celular , Hipertensión Pulmonar , L-Lactato Deshidrogenasa , Lactato Deshidrogenasa 5 , Ácido Láctico , Ratones Endogámicos C57BL , Arteria Pulmonar , Remodelación Vascular , Animales , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Lactato Deshidrogenasa 5/metabolismo , Masculino , Ácido Láctico/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Movimiento Celular , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Hipoxia/complicaciones , Hipoxia/metabolismo , Transducción de Señal , Técnicas de Silenciamiento del Gen , Ratones , Hipoxia de la Célula , Ratas Sprague-Dawley , Ratas , Humanos , Pulmón/patología , Pulmón/irrigación sanguíneaRESUMEN
BACKGROUND: Increasing evidence has shown that hypoxia is a biomarker of tumor proliferation and metastasis. This research aimed to identify a hypoxia-associated gene prognostic index (HAGPI) in head and neck squamous cell carcinoma (HNSCC) and based on HAGPI-defined subgroups to predict prognosis and response to immune checkpoint inhibitors therapy. METHODS: RNA-sequencing transcriptomic data for patients with HNSCC were downloaded from The Cancer Genome Atlas (TCGA). Protein-protein interaction network analysis was performed to select hypoxia-related hub genes. Univariate and multivariate cox regression analyses were used to identify hub genes to develop the HAGPI. Afterward expression data were imported into CIBERSORT to evaluate the relative proportion of 22 immune cells and compared the relative proportions of immune cells between the 2 HAGPI subgroups. The relationship between immunopheno score (IPS) and HAGPI was validated for immune checkpoint inhibitors (ICIs) response in TCGA cohorts. RESULTS: The HAGPI was constructed based on HS3ST1, HK1, PGK1, STC2, SERPINE1, PKLR genes. In high-HAGPI patients, the primary and secondary endpoint events in TCGA and GEO cohorts were significantly lower than low-HAGPI groups (Pâ <â .05). HAGPI-high patients exhibited a poorer prognosis than HAGPI-low patients did. The abundance of M2 macrophages and NK cell were significantly enhanced in the high-HAGPI while T cells regulatory and T cells CD8, were markedly elevated in the low-HAGPI. Meanwhile, patients in the low-HAGPI patients had higher levels of immunosuppressant expression and less aggressive phenotypes. Furthermore, IPS analysis showed that the low-HAGPI group with higher IPS represented a more immunogenic phenotype. CONCLUSION: The current study developed and verified a HAPGI model that can be considered as an independent prognostic biomarker and elucidated the tumor immune microenvironment of HNSCC.
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Neoplasias de Cabeza y Cuello , Inhibidores de Puntos de Control Inmunológico , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/mortalidad , Pronóstico , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Medición de Riesgo/métodos , Mapas de Interacción de Proteínas/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Transcriptoma , Hipoxia , AncianoRESUMEN
The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.
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Glucósidos , Hipertensión Pulmonar , Subunidad alfa del Factor 1 Inducible por Hipoxia , Hipoxia , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Rehmannia , Serina-Treonina Quinasas TOR , Animales , Masculino , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Ratones , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Rehmannia/química , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Glucósidos/farmacología , Hipoxia/tratamiento farmacológico , Hipoxia/fisiopatología , Hipoxia/metabolismo , Transducción de Señal/efectos de los fármacos , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Apoptosis/efectos de los fármacosRESUMEN
Melanin is a crucial pigment in melanomagenesis. Its fluorescence in human tissue is exceedingly weak but can be detected through advanced laser spectroscopy techniques. The spectral profile of melanin fluorescence distinctively varies among melanocytes, nevomelanocytes, and melanoma cells, with melanoma cells exhibiting a notably "red" fluorescence spectrum. This characteristic enables the diagnosis of melanoma both in vivo and in histological samples. Neuromelanin, a brain pigment akin to melanin, shares similar fluorescence properties. Its fluorescence can also be quantified with high spectral resolution using the same laser spectroscopic methods. Documented fluorescence spectra of neuromelanin in histological samples from the substantia nigra substantiate these findings. Our research reveals that the spectral behavior of neuromelanin fluorescence mirrors that of melanin in melanomas. This indicates that the typical red fluorescence is likely influenced by the microenvironment around (neuro)melanin, rather than by direct pigment interactions. Our ongoing studies aim to further explore this distinctive "red" fluorescence. We have observed this red fluorescence spectrum in post-mortem measurements of melanin in benign nevus. The characteristic red spectrum is also evident here (unlike the benign nevus in vivo), suggesting that hypoxia may contribute to this phenomenon. Given the central role of hypoxia in both melanoma development and treatment, as well as in fundamental Parkinson's disease mechanisms, this study discusses strategies aimed at reinforcing the hypothesis that red fluorescence from (neuro)melanin serves as an indicator of hypoxia.
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Melaninas , Melanoma , Espectrometría de Fluorescencia , Humanos , Hipoxia/metabolismo , Melaninas/metabolismo , Melanocitos/metabolismo , Melanoma/metabolismo , Melanoma/patología , Espectrometría de Fluorescencia/métodosRESUMEN
OBJECTIVE: Back to the sources, postoperative nausea and vomiting, hypo- and hypertension, heart rate alterations, and hypoxemia due to laryngospasm might be considered perioperative complications. METHODS: This cross-sectional study was conducted at an Education and Research Hospital between January 2018 and June 2023. The study included a total of 437 cases of thyroid surgery. The demographic data such as age, sex, co-morbidities of the instances, hypotension, hypertension, bradycardia, hypoxemia, and postoperative nausea and vomiting, as well as laboratory data were obtained and analyzed. RESULTS: Of 437 cases, 334 (76%) were females and 103 (24%) were males, with a mean age of 51.83±11.91 years and 55.32±11.87 years, respectively. No statistical significance was realized between the complications, co-morbid diseases, and age. Notably, no liaison between the complications after awakening from the anesthesia and preoperative laboratory parameters was discerned. However, a high but no significant relationship was revealed between the platelet-to-lymphocyte ratio (P/L) in cases with hypoxemia and hypotension. Finally, no significance between laboratory values, bradycardia, hypertension, and postoperative nausea and vomiting was distinguished. CONCLUSION: We postulate that the so-called inflammatory biomarkers measured at the time of preoperative examination in the blood count concept selectively do not enrich for anticipating complications that arise in the perioperative echelon.
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Biomarcadores , Complicaciones Posoperatorias , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Biomarcadores/sangre , Adulto , Anciano , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/sangre , Tiroidectomía/efectos adversos , Náusea y Vómito Posoperatorios/etiología , Náusea y Vómito Posoperatorios/sangre , Hipoxia/sangre , Hipoxia/etiología , Enfermedades de la Tiroides/cirugía , Enfermedades de la Tiroides/sangre , HipertensiónRESUMEN
Pulmonary hypertension (PH) arises from increased pulmonary vascular resistance due to contraction and remodeling of the pulmonary arteries. The structural changes include thickening of the smooth muscle layer from increased proliferation and resistance to apoptosis. The mechanisms underlying apoptosis resistance in PH are not fully understood. In cancer cells, high expression of aquaporin 1 (AQP1), a water channel, is associated with apoptosis resistance. We showed AQP1 protein was expressed in pulmonary arterial smooth muscle cells (PASMCs) and upregulated in preclinical PH models. In this study, we used PASMCs isolated from control male rats and the SU5416 plus hypoxia (SuHx) model to test the role of AQP1 in modulating susceptibility to apoptosis. We found the elevated level of AQP1 in PASMCs from SuHx rats was necessary for resistance to apoptosis and that apoptosis resistance could be conferred by increasing AQP1 in control PASMCs. In exploring the downstream pathways involved, we found AQP1 levels influence the expression of Bcl-2, with enhanced AQP1 levels corresponding to increased Bcl-2 expression, reducing the ratio of BAX to Bcl-2, consistent with apoptosis resistance. These results provide a mechanism by which AQP1 can regulate PASMC fate.
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Apoptosis , Acuaporina 1 , Hipoxia , Indoles , Músculo Liso Vascular , Miocitos del Músculo Liso , Arteria Pulmonar , Pirroles , Animales , Acuaporina 1/metabolismo , Acuaporina 1/genética , Masculino , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/citología , Ratas , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/citología , Pirroles/farmacología , Indoles/farmacología , Hipoxia/metabolismo , Ratas Sprague-Dawley , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Células Cultivadas , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Modelos Animales de EnfermedadRESUMEN
Osteosarcoma (OS) is the most common primary malignant tumour of the bone with high mortality. Here, we comprehensively analysed the hypoxia signalling in OS and further constructed novel hypoxia-related gene signatures for OS prediction and prognosis. This study employed Gene Set Enrichment Analysis (GSEA), Weighted correlation network analysis (WGCNA) and Least absolute shrinkage and selection operator (LASSO) analyses to identify Stanniocalcin 2 (STC2) and Transmembrane Protein 45A (TMEM45A) as the diagnostic biomarkers, which further assessed by Receiver Operating Characteristic (ROC), decision curve analysis (DCA), and calibration curves in training and test dataset. Univariate and multivariate Cox regression analyses were used to construct the prognostic model. STC2 and metastasis were devised to forge the OS risk model. The nomogram, risk score, Kaplan Meier plot, ROC, DCA, and calibration curves results certified the excellent performance of the prognostic model. The expression level of STC2 and TMEM45A was validated in external datasets and cell lines. In immune cell infiltration analysis, cancer-associated fibroblasts (CAFs) were significantly higher in the low-risk group. And the immune infiltration of CAFs was negatively associated with the expression of STC2 (P < 0.05). Pan-cancer analysis revealed that the expression level of STC2 was significantly higher in Esophageal carcinoma (ESCA), Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Lung squamous cell carcinoma (LUSC), and Stomach adenocarcinoma (STAD). Additionally, the higher expression of STC2 was associated with the poor outcome in those cancers. In summary, this study identified STC2 and TMEM45A as novel markers for the diagnosis and prognosis of osteosarcoma, and STC2 was shown to correlate with immune infiltration of CAFs negatively.
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Biomarcadores de Tumor , Neoplasias Óseas , Péptidos y Proteínas de Señalización Intercelular , Aprendizaje Automático , Osteosarcoma , Osteosarcoma/genética , Osteosarcoma/diagnóstico , Osteosarcoma/patología , Humanos , Pronóstico , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Perfilación de la Expresión Génica , Nomogramas , Transcriptoma , Curva ROC , Femenino , Hipoxia/genética , MasculinoRESUMEN
The immune system requires a high energy expenditure to resist pathogen invasion. Macrophages undergo metabolic reprogramming to meet these energy requirements and immunologic activity and polarize to M1-type macrophages. Understanding the metabolic pathway switching in large yellow croaker (Larimichthys crocea) macrophages in response to lipopolysaccharide (LPS) stimulation and whether this switching affects immunity is helpful in explaining the stronger immunity of hypoxia-tolerant L. crocea. In this study, transcript levels of glycolytic pathway genes (Glut1 and Pdk1), mRNA levels or enzyme activities of glycolytic enzymes [hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), and lactate dehydrogenase A (LDHA)], aerobic respiratory enzymes [pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and succinate dehydrogenase (SDH)], metabolites [lactic acid (LA) and adenosine triphosphate (ATP)], levels of bactericidal products [reactive oxygen species (ROS) and nitric oxide (NO)], and transcripts and level changes of inflammatory factors [IL1ß, TNFα, and interferon (IFN) γ] were detected in LPS-stimulated L. crocea head kidney macrophages. We showed that glycolysis was significantly induced, the tricarboxylic acid (TCA) cycle was inhibited, and metabolic reprogramming occurred, showing the Warburg effect when immune cells were activated. To determine the potential regulatory mechanism behind these changes, LcHIF-1α was detected and found to be significantly induced and transferred to the nucleus after LPS stimulation. LcHif-1α interference led to a significant reduction in glycolytic pathway gene transcript expression, enzyme activity, metabolites, bactericidal substances, and inflammatory factor levels; a significant increase in the aerobic respiration enzymes; and decreased migration, invasion, and phagocytosis. Further ultrastructural observation by electron microscopy showed that fewer microspheres contained phagocytes and that more cells were damaged after LcHif-1α interference. LcHif-1α overexpression L. crocea head kidney macrophages showed the opposite trend, and promoter activities of Ldha and Il1ß were significantly enhanced after LcHif-1α overexpression in HEK293T cells. Our data showed that LcHIF-1α acted as a metabolic switch in L. crocea macrophages and was important in polarization. Hypoxia-tolerant L. crocea head kidney showed a stronger Warburg effect and inhibited the TCA cycle, higher metabolites, and bactericidal substance levels. These results collectively revealed that LcHif-1α may promote the functional activities of head kidney macrophages in protecting hypoxia-tolerant L. crocea from Aeromonas hydrophila infection.
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Aeromonas hydrophila , Enfermedades de los Peces , Infecciones por Bacterias Gramnegativas , Subunidad alfa del Factor 1 Inducible por Hipoxia , Macrófagos , Perciformes , Animales , Perciformes/inmunología , Perciformes/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/microbiología , Enfermedades de los Peces/metabolismo , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/veterinaria , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Aeromonas hydrophila/fisiología , Aeromonas hydrophila/inmunología , Lipopolisacáridos/inmunología , Glucólisis , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Activación de Macrófagos/inmunología , Hipoxia/inmunología , Hipoxia/metabolismo , Riñón Cefálico/inmunología , Riñón Cefálico/metabolismoRESUMEN
Hypoxia, as a prominent feature of the tumor microenvironment, has a profound impact on the multicomponent changes within this environment. Under hypoxic conditions, the malignant phenotype of tumor cells, the variety of cell types within the tumor microenvironment, as well as intercellular communication and material exchange, undergo complex alterations. These changes provide significant prospects for exploring the mechanisms of tumor development under different microenvironmental conditions and for devising therapeutic strategies. Exosomes secreted by tumor cells and stromal cells are integral components of the tumor microenvironment, serving as crucial mediators of intercellular communication and material exchange, and have consequently garnered increasing attention from researchers. This review focuses on the mechanisms by which hypoxic conditions promote the release of exosomes by tumor cells and alter their encapsulated contents. It also examines the effects of exosomes derived from tumor cells, immune cells, and other cell types under hypoxic conditions on the tumor microenvironment. Additionally, we summarize current research progress on the potential clinical applications of exosomes under hypoxic conditions and propose future research directions in this field.
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Comunicación Celular , Exosomas , Neoplasias , Microambiente Tumoral , Exosomas/metabolismo , Humanos , Comunicación Celular/fisiología , Neoplasias/metabolismo , Neoplasias/patología , Animales , Hipoxia de la Célula/fisiología , Hipoxia Tumoral , Hipoxia/metabolismoRESUMEN
Occupational pulmonary diseases (OPDs) pose a significant global health challenge, contributing to high mortality rates. This review delves into the pathophysiology of hypoxia and the safety of intermittent hypoxic conditioning (IHC) in OPD patients. By examining sources such as PubMed, Relemed, NLM, Scopus, and Google Scholar, the review evaluates the efficacy of IHC in clinical outcomes for OPD patients. It highlights the complexities of cardiovascular and respiratory regulation dysfunctions in OPDs, focusing on respiratory control abnormalities and the impact of intermittent hypoxic exposures. Key areas include the physiological effects of hypoxia, the role of hypoxia-inducible factor-1 alpha (HIF-1α) in occupational lung diseases, and the links between brain ischemia, stroke, and OPDs. The review also explores the interaction between intermittent hypoxic exposures, mitochondrial energetics, and lung physiology. The potential of IHE to improve clinical manifestations and underlying pathophysiology in OPD patients is thoroughly examined. This comprehensive analysis aims to benefit molecular pathologists, pulmonologists, clinicians, and physicians by enhancing understanding of IHE's clinical benefits, from research to patient care, and improving clinical outcomes for OPD patients.
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Hipoxia , Enfermedades Pulmonares , Enfermedades Profesionales , Humanos , Hipoxia/fisiopatología , Enfermedades Pulmonares/fisiopatología , Enfermedades Profesionales/fisiopatología , Enfermedades Profesionales/terapia , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Pulmón/fisiopatologíaRESUMEN
Our group previously showed that genetic or pharmacological inhibition of the cystine/glutamate antiporter, system xc -, mitigates excitotoxicity after anoxia by increasing latency to anoxic depolarization, thus attenuating the ischaemic core. Hypoxia, however, which prevails in the ischaemic penumbra, is a condition where neurotransmission is altered, but excitotoxicity is not triggered. The present study employed mild hypoxia to further probe ischaemia-induced changes in neuronal responsiveness from wild-type and xCT KO (xCT-/-) mice. Synaptic transmission was monitored in hippocampal slices from both genotypes before, during and after a hypoxic episode. Although wild-type and xCT-/- slices showed equal suppression of synaptic transmission during hypoxia, mutant slices exhibited a persistent potentiation upon re-oxygenation, an effect we termed 'post-hypoxic long-term potentiation (LTP)'. Blocking synaptic suppression during hypoxia by antagonizing adenosine A1 receptors did not preclude post-hypoxic LTP. Further examination of the induction and expression mechanisms of this plasticity revealed that post-hypoxic LTP was driven by NMDA receptor activation, as well as increased calcium influx, with no change in paired-pulse facilitation. Hence, the observed phenomenon engaged similar mechanisms as classical LTP. This was a remarkable finding as theta-burst stimulation-induced LTP was equivalent between genotypes. Importantly, post-hypoxic LTP was generated in wild-type slices pretreated with system xc - inhibitor, S-4-carboxyphenylglycine, thereby confirming the antiporter's role in this phenomenon. Collectively, these data indicate that system xc - interference enables neuroplasticity in response to mild hypoxia, and, together with its regulation of cellular damage in the ischaemic core, suggest a role for the antiporter in post-ischaemic recovery of the penumbra.
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Sistema de Transporte de Aminoácidos y+ , Hipocampo , Hipoxia , Potenciación a Largo Plazo , Ratones Noqueados , Animales , Potenciación a Largo Plazo/fisiología , Hipocampo/metabolismo , Ratones , Hipoxia/fisiopatología , Hipoxia/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Masculino , Transmisión Sináptica/fisiología , Ratones Endogámicos C57BL , Ácido Glutámico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The present study aimed to investigate the occurrence of ferroptosis in mouse hippocampal tissue and changes in related pathways after exposure to high-altitude hypoxia. A low-pressure hypoxia model was established using a high-altitude environment at 4 010 m. HE staining was used to observe morphological changes in mouse hippocampal tissue, immunohistochemical staining was used to observe lipid peroxidation levels in hippocampal tissue, and corresponding kits were used to measure malondialdehyde (MDA), reduced glutathione (GSH), and Fe2+ levels in hippocampal tissue. Western blot was used to detect glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthase long chain family member 4 (ACSL4). The results showed that, compared with the plain control group, the mice exposed to high-altitude hypoxia for 1, 3, 7, and 14 d exhibited significant pathological damage, disordered arrangement, and obvious nuclear condensation in the dentate gyrus of the hippocampus. Compared with the plain control group, high-altitude hypoxia exposure increased 4-hydroxynonenal (4-HNE) content in the dentate gyrus and hippocampal MDA content, whereas significantly decreased hippocampal GSH content. Compared with the plain control group, the Fe2+ content in the hippocampus of mice exposed to high-altitude hypoxia for 14 d significantly increased. Compared with the plain control group, the protein expression levels of GPX4, FTH1, FPN1, TfR1, and FSP1 in the hippocampus of mice exposed to high-altitude hypoxia were significantly down-regulated (SLC7A11 was significantly down-regulated only in the 7-d high-altitude hypoxia exposure group), while the protein expression level of ACSL4 was only significantly up-regulated in the 14-d high-altitude hypoxia exposure group. These results suggest that exposure to high-altitude hypoxia for 14 d can reduce GSH synthesis in mouse hippocampus, down-regulate GPX4 expression, lead to GSH metabolism disorders, inhibit iron storage and efflux, promote lipid peroxidation reaction, and inhibit CoQ10H2's anti-lipid peroxidation effect, ultimately leading to ferroptosis.
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Mal de Altura , Ferroptosis , Hipocampo , Hipoxia , Animales , Ferroptosis/fisiología , Hipocampo/metabolismo , Ratones , Hipoxia/metabolismo , Hipoxia/fisiopatología , Masculino , Mal de Altura/metabolismo , Mal de Altura/fisiopatología , Peroxidación de Lípido , Receptores de Transferrina/metabolismo , Altitud , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Glutatión/metabolismo , Malondialdehído/metabolismo , Hierro/metabolismo , Proteínas de Transporte de Catión/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genéticaRESUMEN
The onset and progression of atherosclerosis are closely linked to the involvement of macrophages. While the contribution of NLRP3 inflammasome activation to the creation of a local highly inflammatory microenvironment is well recognized, the precise triggers remain unclear. In this study, we aimed to investigate the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia-induced glycolysis involving PFKFB3 in the development of atherosclerosis. To develop an atherosclerosis model, we selected ApoE knockout mice treated with a high-fat western diet. We then quantified the expression of HIF-1α, PFKFB3, and NLRP3. In addition, we administered the PFKFB3 inhibitor PFK158 during atherosclerosis modeling. The glycolytic activity was subsequently determined through 18F-FDG micro-PET/CT, ex vivo glucose uptake, and ECAR analysis. Furthermore, we employed lipopolysaccharide (LPS) and TNF-α to induce the differentiation of bone marrow-derived macrophages (BMDMs) into M1-like phenotypes under both hypoxic and normoxic conditions. Our histological analyses revealed the accumulation of PFKFB3 in human atherosclerotic plaques, demonstrating colocalization with NLRP3 expression and macrophages. Treatment with PFK158 reduced glycolytic activity and NLRP3 inflammasome activation, thereby mitigating the occurrence of atherosclerosis. Mechanistically, hypoxia promoted glycolytic reprogramming and NLRP3 inflammasome activation in BMDMs. Subsequent blocking of either HIF-1α or PFKFB3 downregulated the NLRP3/Caspase-1/IL-1ß pathway in hypoxic BMDMs. Our study demonstrated that the HIF-1α/PFKFB3/NLRP3 axis serves as a crucial mechanism for macrophage inflammation activation in the emergence of atherosclerosis. The therapeutic potential of PFKFB3 inhibition may represent a promising strategy for atheroprotection.
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Aterosclerosis , Glucólisis , Inflamasomas , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Fosfofructoquinasa-2 , Animales , Fosfofructoquinasa-2/metabolismo , Fosfofructoquinasa-2/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Ratones , Macrófagos/metabolismo , Inflamasomas/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Masculino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Hipoxia/metabolismo , Ratones NoqueadosRESUMEN
The retina is one of the highest metabolically active tissues with a high oxygen consumption, so insufficient blood supply leads to visual impairment. The incidence of related conditions is increasing; however, no effective treatment without side effects is available. Furthermore, the pathomechanism of these diseases is not fully understood. Our aim was to develop an optimal ischemic retinopathy mouse model to investigate the retinal damage in a time-dependent manner. Retinal ischemia was induced by bilateral common carotid artery occlusion (BCCAO) for 10, 13, 15 or 20 min, or by right permanent unilateral common carotid artery occlusion (UCCAO). Optical coherence tomography was used to follow the changes in retinal thickness 3, 7, 14, 21 and 28 days after surgery. The number of ganglion cells was evaluated in the central and peripheral regions on whole-mount retina preparations. Expression of glial fibrillary acidic protein (GFAP) was analyzed with immunohistochemistry and Western blot. Retinal degeneration and ganglion cell loss was observed in multiple groups. Our results suggest that the 20 min BCCAO is a good model to investigate the consequences of ischemia and reperfusion in the retina in a time-dependent manner, while the UCCAO causes more severe damage in a short time, so it can be used for testing new drugs.
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Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía , Hipoxia , Isquemia , Retina , Tomografía de Coherencia Óptica , Animales , Ratones , Isquemia/metabolismo , Isquemia/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Retina/metabolismo , Retina/patología , Hipoxia/metabolismo , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Enfermedades de la Retina/etiología , Masculino , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Ratones Endogámicos C57BL , Factores de TiempoRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with limited therapeutic options. Hypoxia is a common feature of the tumor microenvironment that reportedly promotes tumorigenesis. Long non-coding RNAs (lncRNAs) are a class of regulatory molecules with diverse functions in cancer biology. This study aimed to identify hypoxia-induced lncRNAs associated with HCC and evaluate their potential as prognostic and therapeutic biomarkers. METHODS: We employed microarray and The Cancer Genome Atlas (TCGA) data to identify hypoxia-induced lncRNAs in HCC. Subsequently, we focused on CTD-2510F5.4, a candidate lncRNA, and predicted its functional roles in HCC using Gene Ontology (GO) and Guilt-by-Association (GBA) analyses. We validated its expression under hypoxia in Huh7 and HepG2 cells using RT-PCR. Functional assays, including CCK8, wound-healing, and transwell assays, were performed to assess the effects of CTD-2510F5.4 overexpression on HCC cell proliferation, invasion, and metastasis potential. Furthermore, we investigated the association between CTD-2510F5.4 expression and patient prognosis, tumor mutation signature, immune microenvironment characteristics, and therapeutic response to different treatment modalities. RESULTS: Our data demonstrated a significant upregulation of CTD-2510F5.4 expression in response to hypoxia. Functional enrichment analyses revealed the involvement of CTD-2510F5.4 in cell cycle regulation, E2F targets, G2M checkpoint control, and MYC signaling pathways. Functionally, CTD-2510F5.4 overexpression promoted HCC cell proliferation, invasion, and metastasis. Patients with high CTD-2510F5.4 expression exhibited a worse prognosis, a higher prevalence of TP53 mutations, increased infiltration by immunosuppressive regulatory T cells, elevated expression of immune checkpoint molecules, and higher TIDE scores indicative of immune dysfunction and exclusion. Notably, patients with low CTD-2510F5.4 expression displayed greater sensitivity to immunotherapy and antiangiogenic therapy, while those with high expression responded better to chemotherapy. CONCLUSION: Our findings suggest that CTD-2510F5.4 plays a critical role in HCC progression and immune modulation. Its potential as a prognostic biomarker and a predictor of therapeutic response warrants further investigation for personalized treatment strategies in HCC patients.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , ARN Largo no Codificante , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Microambiente Tumoral/genética , ARN Largo no Codificante/genética , Pronóstico , Proliferación Celular/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Células Hep G2 , Hipoxia/genética , Movimiento Celular/genéticaRESUMEN
Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which is related to tumorigenesis and progression. We explored the possible mechanisms by which OSA may promote the development of non-small cell lung cancer (NSCLC). In this study, NSCLC cells with and without miR-106a-5p inhibition were exposed to IH or room air (RA), and subsequently, exosomes were extracted and identified. Macrophages were incubated with these exosomes to detect the expression of the STAT3 signaling pathway and M2-type macrophage markers, as well as the effect of the macrophages on the malignancy of NSCLC cells. A nude mouse tumorigenesis model was constructed to detect the effects of exosomal miR-106a-5p on M2 macrophage polarization and NSCLC cell malignancy. Our results showed that IH exosomes promoted the polarization of M2 macrophages, thereby promoting the proliferation, invasion, and metastasis of NSCLC cells. Further, Based on microarray analysis of RA and IH exosomes, we discovered that miR-106a-5p, transferred to the macrophages through exosomes, participated in this mechanism by promoting M2 macrophage polarization via down-regulating PTEN and activating the STAT3 signaling pathway in vitro and in vivo. For patients with NSCLC and OSA, exosomal miR-106a-5p levels showed a positive relation to AHI. Exosomal miR-106a-5p represents a potential therapeutic target among patients with concomitant cancer and NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Exosomas , Neoplasias Pulmonares , Ratones Desnudos , MicroARNs , Factor de Transcripción STAT3 , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Humanos , Animales , Exosomas/metabolismo , Exosomas/genética , Ratones , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Masculino , Macrófagos/metabolismo , Línea Celular Tumoral , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Proliferación Celular , Apnea Obstructiva del Sueño/genética , Apnea Obstructiva del Sueño/metabolismo , Transducción de Señal , Hipoxia/metabolismo , Hipoxia/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Surprisingly, despite the high prevalence of metformin use in type 2 diabetes (T2D) patients with heart disease, limited safety data is available regarding metformin use in patients with acute and critical heart disease. METHODS: In this single-center retrospective study, patients admitted to the cardiology department for heart failure (HF) or acute coronary syndrome (ACS) between December 2013 and December 2021 and who underwent arterial blood gas analysis at admission with an estimated glomerular clearance rate of ≥45 ml/min/1.73 m2 were identified. The incidences of hyperlactatemia, acidosis, and 30-day in-hospital mortality were compared between preadmission metformin users and nonusers. RESULTS: Of 526 admissions, 193/193 metformin users/nonusers were selected in a propensity score-matched model. Metformin users had greater lactate levels (2.55 ± 2.07 mmol/l vs. 2.00 ± 1.80 mmol/l P < 0.01), a greater incidence of hyperlactatemia [odds ratio (OR) = 2.55; 95% confidence interval (CI), 1.63-3.98; P < 0.01] and acidosis (OR = 1.78; 95% CI, 1.00-3.16; P < 0.05) at admission and a greater incidence of in-hospital mortality (OR = 3.83; 95% CI, 1.05-13.94; P < 0.05), especially those with HF/acute myocardial infarction, elderly age, or without preadmission insulin use. CONCLUSIONS: Our results suggest that, compared to metformin nonusers, preadmission use of metformin may be associated with a greater incidence of hyperlactatemia and acidosis at admission and greater 30-day in-hospital mortality among T2D patients with HF or ACS at high risk of hypoxia, particularly those without preadmission insulin use. The safety of metformin in this population needs to be confirmed in prospective controlled trials.
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Diabetes Mellitus Tipo 2 , Mortalidad Hospitalaria , Hiperlactatemia , Hipoglucemiantes , Metformina , Humanos , Metformina/uso terapéutico , Metformina/efectos adversos , Masculino , Femenino , Mortalidad Hospitalaria/tendencias , Estudios Retrospectivos , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Hiperlactatemia/epidemiología , Hiperlactatemia/sangre , Hiperlactatemia/inducido químicamente , Incidencia , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Persona de Mediana Edad , Hipoxia/epidemiología , Hipoxia/mortalidad , Hipoxia/sangre , Admisión del Paciente/tendencias , Cardiopatías/epidemiología , Cardiopatías/mortalidad , Cardiopatías/sangre , Anciano de 80 o más Años , Factores de RiesgoRESUMEN
BACKGROUND: Apnea and intermittent hypoxemia (IH) are common developmental disorders in infants born earlier than 37 weeks' gestation. Caffeine administration has been shown to lower the incidence of these disorders in preterm infants. Cessation of caffeine treatment is based on different post-menstrual ages (PMA) and resolution of symptoms. There is uncertainty about the best timing for caffeine discontinuation. OBJECTIVES: To evaluate the effects of early versus late discontinuation of caffeine administration in preterm infants. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, and three trial registries in August 2023; we applied no date limits. We checked the references of included studies and related systematic reviews. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in preterm infants born earlier than 37 weeks' gestation, up to a PMA of 44 weeks and 0 days, who received caffeine for any indication for at least seven days. We compared three different strategies for caffeine cessation: 1. at different PMAs, 2. before or after five days without symptoms, and 3. at a predetermined PMA versus at the resolution of symptoms. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were: restarting caffeine therapy, intubation within one week of treatment discontinuation, and the need for non-invasive respiratory support within one week of treatment discontinuation. Secondary outcomes were: number of episodes of apnea in the seven days after treatment discontinuation, number of infants with at least one episode of apnea in the seven days after treatment discontinuation, number of episodes of intermittent hypoxemia (IH) within seven days of treatment discontinuation, number of infants with at least one episode of IH in the seven days after of treatment discontinuation, all-cause mortality prior to hospital discharge, major neurodevelopmental disability, number of days of respiratory support after treatment discontinuation, duration of hospital stay, and cost of neonatal care. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included three RCTs (392 preterm infants). Discontinuation of caffeine at PMA less than 35 weeks' gestation versus PMA equal to or longer than 35 weeks' gestation This comparison included one single completed RCT with 98 premature infants with a gestational age between 25 + 0 and 32 + 0 weeks at birth. All infants had discontinued caffeine treatment for five days at randomization. The infants received either an oral loading dose of caffeine citrate (20 mg/kg) at randomization followed by oral maintenance dosage (6 mg/kg/day) until 40 weeks PMA, or usual care (controls), during which caffeine was stopped before 37 weeks PMA. Early cessation of caffeine administration in preterm infants at PMA less than 35 weeks' gestation may result in an increase in the number of IH episodes in the seven days after discontinuation of treatment, compared to prolonged caffeine treatment beyond 35 weeks' gestation (mean difference [MD] 4.80, 95% confidence interval [CI] 2.21 to 7.39; 1 RCT, 98 infants; low-certainty evidence). Early cessation may result in little to no difference in all-cause mortality prior to hospital discharge compared to late discontinuation after 35 weeks PMA (risk ratio [RR] not estimable; 98 infants; low-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, number of episodes of apnea, number of infants with at least one episode of apnea in the seven days after discontinuation of treatment, or number of infants with at least one episode of IH in the seven days after discontinuation of treatment. Discontinuation based on PMA versus resolution of symptoms This comparison included two RCTs with a total of 294 preterm infants. Discontinuing caffeine at the resolution of symptoms compared to discontinuing treatment at a predetermined PMA may result in little to no difference in all-cause mortality prior to hospital discharge (RR 1.00, 95% CI 0.14 to 7.03; 2 studies, 294 participants; low-certainty evidence), or in the number of infants with at least one episode of apnea within the seven days after discontinuing treatment (RR 0.60, 95% CI 0.31 to 1.18; 2 studies; 294 infants; low-certainty evidence). Discontinuing caffeine based on the resolution of symptoms probably results in more infants with IH in the seven days after discontinuation of treatment (RR 0.38, 95% CI 0.20 to 0.75; 1 study; 174 participants; moderate-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, or number of episodes of IH in the seven days after treatment discontinuation. Adverse effects In the Rhein 2014 study, five of the infants randomized to caffeine had the caffeine treatment discontinued at the discretion of the clinical team, because of tachycardia. The Pradhap 2023 study reported adverse events, including recurrence of apnea of prematurity (15% in the short and 13% in the regular course caffeine therapy group), varying severities of bronchopulmonary dysplasia, hyperglycemia, extrauterine growth restriction, retinopathy of prematurity requiring laser treatment, feeding intolerance, osteopenia, and tachycardia, with no significant differences between the groups. The Prakash 2021 study reported that adverse effects of caffeine therapy for apnea of prematurity included tachycardia, feeding intolerance, and potential neurodevelopmental impacts, though most were mild and transient. We identified three ongoing studies. AUTHORS' CONCLUSIONS: There may be little or no difference in the incidence of all-cause mortality and apnea in infants who were randomized to later discontinuation of caffeine treatment. However, the number of infants with at least one episode of IH was probably reduced with later cessation. No data were found to evaluate the benefits and harms of later caffeine discontinuation for: restarting caffeine therapy, intubation within one week of treatment discontinuation, or need for non-invasive respiratory support within one week of treatment discontinuation. Further studies are needed to evaluate the short-term and long-term effects of different caffeine cessation strategies in premature infants.